The membrane glycoprotein MRC OX-2 (CD200) is expressed in several lymphoid malignancies. However, the diagnostic usefulness and potential prognostic importance of CD200 expression have not been rigorously examined. We show that CD200 is uniformly expressed in chronic lymphocytic leukemia (CLL) and absent in mantle cell lymphoma (MCL). It is important to note that expression of CD200 is retained even in CLLs with immunophenotypic aberrancies, making CD200 a particularly useful marker for discrimination between these cases and MCL. CD200 is expressed in nearly all precursor B-lymphoblastic leukemias, with aberrant overexpression or underexpression compared with normal B-cell progenitors in 55% of cases. More than 70% of plasma cell myelomas (PCMs) expressed CD200, and loss of CD200 expression in PCM may be associated with more clinically aggressive disease. CD200 is expressed in several hematolymphoid neoplasms. Analysis of its expression has several diagnostic and potentially prognostic applications in the flow cytometric evaluation of lymphoid malignancies.